Endogenous Acetylcholine Limits α1‐Adrenergic Vasoconstriction During Exercise in Humans

Abstract

Sympathetic vasoconstriction is markedly attenuated within the vasculature of contracting compared to quiescent skeletal muscle (“functional sympatholysis”), yet the mechanisms that modulate post‐junctional α‐adrenergic signaling in active muscle remain poorly understood. In rodents, application of the endothelium‐dependent agonist acetylcholine (ACh) blunts sympathetic vasoconstriction in skeletal muscle resistance vessels, and we have recently demonstrated that intra‐arterial administration of ACh enhances functional sympatholysis in humans. Thus, we sought to determine whether endogenous ACh is involved in this integrative control of vascular tone during exercise. In 16 healthy volunteers (8 F, 8 M; 26 ± 1 yrs), we assessed the vasoconstrictor response to intra‐arterial phenylephrine (PE; α1 agonist) at rest and during rhythmic handgrip exercise under control conditions and during local inhibition of muscarinic ACh receptors via intra‐arterial atropine. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) at rest and during 4 min of dynamic handgrip contractions at two exercise intensities (15 and 25% of maximal voluntary contraction, MVC). Adenosine was infused during the resting trials to elevate FBF to levels similar to those observed during exercise. After the vascular response to exercise or adenosine reached steady‐state, we assessed vasoconstriction during infusion of PE for 2 min. The magnitude of sympatholysis was calculated as the percent reduction in vasoconstriction during exercise compared to rest. As expected, the vasoconstrictor response (Δ FVC) to PE was attenuated during exercise at 15 (−20 ± 2%) and 25% MVC (−12 ± 2%) compared with rest (−40 ± 4%; P < 0.05), indicating functional sympatholysis. Atropine did not affect sensitivity to PE at rest (−38 ± 4%; P = 0.60). During 15% MVC exercise, atropine augmented vasoconstriction to PE in women (−25 ± 2 vs. −19 ± 2%, P < 0.05), whereas it did not affect the response in men (−22 ± 2 vs. −22 ± 3%, P = 0.88). During higher intensity exercise, atropine reduced the magnitude of functional sympatholysis by ~50% such that a greater degree of vasoconstriction occurred in response to PE in both women (−22 ± 4 vs. −11 ± 4%, P < 0.05) and men (−22 ± 2 vs. −12 ± 2%, P < 0.05) compared to control conditions. These findings demonstrate that inhibition of muscarinic receptors reduces the ability of contracting muscle to limit sympathetic vasoconstriction in an intensity‐ and sex‐dependent manner, supporting a novel, physiological role for ACh in functional sympatholysis in humans.Support or Funding InformationSupported by HL119337 & HL142240This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.